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首页> 美国卫生研究院文献>other >A Novel allosteric pathway of thrombin inhibition: Exosite II mediated potent inhibition of thrombin by chemo-enzymatic sulfated dehydropolymers of 4-hydroxycinnamic acids
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A Novel allosteric pathway of thrombin inhibition: Exosite II mediated potent inhibition of thrombin by chemo-enzymatic sulfated dehydropolymers of 4-hydroxycinnamic acids

机译：凝血酶抑制的新型变构途径：Exosite II介导的4-羟基肉桂酸化学酶促硫酸化脱氢酶对凝血酶的有效抑制

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摘要

Thrombin and factor Xa, two important pro-coagulant proteinases, can be regulated through direct and indirect inhibition mechanisms. Recently, we designed sulfated dehydropolymers (DHPs) of 4-hydroxycinnamic acids that displayed interesting anticoagulant properties (Monien, B. H., Henry, B. L., Raghuraman, A., Hindle, M., and Desai, U. R. (2006) Bioorg. Med. Chem. 14, 7988–7998). To better understand their mechanism of action, we studied the direct inhibition of thrombin, factor Xa, factor IXa, and factor VIIa by CDSO3, FDSO3, and SDSO3, three analogs of sulfated DHPs. All three sulfated DHPs displayed a 2–3-fold preference for direct inhibition of thrombin over factor Xa, whereas this preference for inhibiting thrombin over factor IXa and factor VIIa increased to 17–300-fold, suggesting a high level of selectivity. Competitive binding studies with a thrombin-specific chromogenic substrate, a fluorescein-labeled hirudin peptide, bovine heparin, enoxaparin, and a heparin octasaccharide suggest that CDSO3 preferentially binds in or near anion-binding exosite II of thrombin. Studies of the hydrolysis of H-D-hexahydrotyrosol-Ala-Arg-p-nitroanilide indicate that CDSO3 inhibits thrombin through allosteric disruption of the catalytic apparatus, specifically through the catalytic step. Overall, designed sulfated DHPs appear to be the first molecules that bind primarily in the region defined by exosite II and allosterically induce thrombin inhibition. The molecules are radically different in structure from all the current clinically used anticoagulants and thus represent a novel class of potent dual thrombin and factor Xa inhibitors.
机译：凝血酶和Xa因子是两种重要的促凝血蛋白酶，可以通过直接和间接抑制机制进行调节。最近，我们设计了4-羟基肉桂酸的硫酸化脱氢聚合物（DHP），它们显示出有趣的抗凝特性（Monien，BH，Henry，BL，Raghuraman，A.，Hindle，M.和Desai，UR（2006）Bioorg。Med。Chem 14，7988–7998）。为了更好地了解它们的作用机理，我们研究了硫酸化DHP的三种类似物CDSO3，FDSO3和SDSO3对凝血酶，Xa因子，IXa因子和VIIa因子的直接抑制作用。所有三种硫酸化的DHP都显示出对凝血酶的直接抑制优于对因子Xa的2-3倍，而对抑制凝血酶的对IXa和VIIa因子的偏好增加到17-300倍，表明具有较高的选择性。对凝血酶特异性生色底物，荧光素标记的水rud素肽，牛肝素，依诺肝素和肝素八糖的竞争性结合研究表明，CDSO3优先结合在凝血酶的阴离子结合异位点II中或附近。对H-D-六氢酪醇-Ala-Arg-对硝基苯胺水解的研究表明，CDSO3通过催化装置的变构破坏，特别是通过催化步骤，抑制凝血酶。总体而言，设计的硫酸化DHP似乎是主要在外位II定义的区域主要结合并变构诱导凝血酶抑制的第一个分子。这些分子在结构上与目前所有临床使用的抗凝剂完全不同，因此代表了一类新型的强效双重凝血酶和Xa因子抑制剂。

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